8-aza-bicyclo[3.2.1]octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors

ABSTRACT

This invention relates to novel 8-aza-bicyclo[3.2.1]octane derivatives useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.

TECHNICAL FIELD

This invention relates to novel 8-aza-bicyclo[3.2.1]octane derivativesuseful as monoamine neurotransmitter re-uptake inhibitors.

In other aspects the invention relates to the use of these compounds ina method for therapy and to pharmaceutical compositions comprising thecompounds of the invention.

BACKGROUND ART

WO 97/30997 (NeuroSearch A/S) describes tropane derivatives active asneurotransmitter re-uptake inhibitors.

However, there is a continued strong need to find compounds with anoptimised biochemical profile as regards the activity on reuptake of themonoamine neurotransmitters serotonin, dopamine and noradrenaline, suchas the ratio of the serotonin reuptake versus the noradrenaline anddopamine activity.

SUMMARY OF THE INVENTION

In its first aspect, the invention provides a 8-aza-bicyclo[3.2.1]octanederivative of the Formula I:

or any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof,

-   wherein R, R² and R³ are as defined below.

In its second aspect, the invention provides a pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundof the invention, or any of its isomers or any mixture of its isomers,or a pharmaceutically acceptable salt thereof, together with at leastone pharmaceutically acceptable carrier, excipient or diluent.

In a further aspect, the invention provides the use of a compound of theinvention, or any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition for the treatment, prevention or alleviationof a disease or a disorder or a condition of a mammal, including ahuman, which disease, disorder or condition is responsive to inhibitionof monoamine neurotransmitter re-uptake in the central nervous system.

In a still further aspect the invention relates to a method fortreatment, prevention or alleviation of a disease or a disorder or acondition of a living animal body, including a human, which disorder,disease or condition is responsive to responsive to inhibition ofmonoamine neurotransmitter re-uptake in the central nervous system,which method comprises the step of administering to such a living animalbody in need thereof a therapeutically effective amount of a compound ofthe invention, or any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

Tropane Derivatives

In its first aspect the present invention provides a8-aza-bicyclo[3.2.1]octane derivative of formula I:

or any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof,

-   wherein-   R represents hydrogen or alkyl;-   R² represents —CH₂—X—R^(a);-   wherein X represents —O— or —S—;-   R^(a) represents

-   -   wherein R^(b) and R^(c) are independently selected from the        group consisting of:        -   halo, hydroxy, amino, cyano, nitro, trifluoromethyl,            trifluoromethoxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl,            cycloalkylalkyl, alkenyl, and alkynyl;

-   or R^(a) represents naphthyl;    -   which naphthyl is optionally substituted with substituted with        one or more substituents selected from the group consisting of:        -   halo, hydroxy, amino, cyano, nitro, trifluoromethyl,            trifluoromethoxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl,            cycloalkylalkyl, alkenyl, and alkynyl

-   R³ represents phenyl or naphthyl;    -   which phenyl or naphthyl is optionally substituted with        substituted with one or more substituents selected from the        group consisting of:        -   halo, hydroxy, amino, cyano, nitro, trifluoromethyl,            trifluoromethoxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl,            cycloalkylalkyl, alkenyl, and alkynyl;

-   or R³ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,    alkenyl, or alkynyl;    -   which alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, or alkynyl is        optionally substituted with one or more substituents from the        group consisting of:        -   halo, hydroxy, amino, cyano, nitro, trifluoromethyl,            trifluoromethoxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl,            cycloalkylalkyl, alkenyl, and alkynyl.

In one embodiment, R represents hydrogen. In a further embodiment, Rrepresents alkyl, such as methyl. In a still further embodiment, Rrepresents hydrogen or methyl.

In a further embodiment, X represents —O—. In a still furtherembodiment, X represents —S—.

In a further embodiment, R^(a) represents

In a still further embodiment, R^(b) is halo, such as chloro or fluoro.In one embodiment, R^(b) is chloro. In another embodiment, R^(b) isfluoro. In a further embodiment, R^(c) is halo, such as chloro orfluoro. In one embodiment, R^(c) is chloro. In another embodiment, R^(c)is fluoro. In a further embodiment, R^(b) is alkoxy, such as methoxy. Ina still further embodiment, R^(c) is alkoxy, such as methoxy. In afurther embodiment, R^(b) is halo and R^(c) is halo. In a specialembodiment, R^(a) represents 2,3-dichlorophenyl. In a furtherembodiment, R^(a) represents 2,3-difluorophenyl. In a still furtherembodiment, R^(a) represents 2-chloro-3-fluorophenyl. In a furtherembodiment, R^(a) represents 2,3-dimethoxyphenyl.

In a further embodiment, R^(a) represents naphthyl, such asnaphthalene-1-yl or naphthalene-2-yl. In a special embodiment, R^(a)represents naphthalene-1-yl. In a further embodiment, R^(a) representsnaphthalene-2-yl.

In a special embodiment, R² represents 2,3-dichlorophenoxymethyl. In afurther embodiment, R² represents 2,3-dichlorophenylsulfanylmethyl. In afurther embodiment, R² represents 2,3-difluorophenoxymethyl. In afurther embodiment, R² represents 2-chloro-3-fluorophenoxymethyl. In afurther embodiment, R² represents 2,3-dimethoxyhenoxymethyl. In afurther embodiment, R² represents 1-naphthyloxy-methyl.

In a still further embodiment, R³ represents optionally substitutedphenyl. In a special embodiment, R³ represents phenyl optionallysubstituted with one or more halo. In a special embodiment, R³represents 3-halophenyl. In a further embodiment, R³ represents phenyl,3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl or 3,4-dichlorophenyl.

In a further embodiment, R³ represents alkyl, such as propyl or butyl.In a special embodiment, R³ represents ethyl. In a further embodiment,R³ represents propyl, such as iso-propyl. In a further specialembodiment, R³ represents butyl, such as 1-butyl.

In a still further embodiment, R³ represents cycloalkyl. In a specialembodiment, R³ represents cyclopropyl.

In a further embodiment, R³ represents hydrogen, alkyl or cycloalkyl. Ina still further embodiment, R³ represents hydrogen.

In a special embodiment of the compound of formula I,

-   R represents hydrogen or methyl;-   R^(a) represents 2,3-dihalophenyl, 2,3-dimethoxyphenyl or naphthyl;    and-   R³ represents hydrogen, alkyl, cycloalkyl or phenyl optionally    substituted with one or more halo.

In a further special embodiment of the compound of formula I,

-   R represents hydrogen or methyl;-   R^(a) represents 2,3-dichlorophenyl or naphthyl; and-   R³ represents alkyl or phenyl optionally substituted with one or    more chloro.

In a special embodiment the chemical compound of the invention is

-   (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(1-Naphthaleneoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2S,3S)-2-(2,3-Chlorophenylthiomethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2S,3R)-2-(2,3-Dichloro-phenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2S,3R)-2-(1-Naphthaleneoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2S,3R)-2-(2,3-Chlorophenylthiomethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dichloraphenoxymethyl-8-methyl-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-(n-butyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dichlorophenylthiomethyl)-8-methyl-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dimethoxyphenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2R-2-(2,3-Dichlorophenoxymethyl)-8-methyl-aza-bicyclo[3.2.1]octane;-   (2R)-2-(1-Naphthyloxymethyl)-8-methyl-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-fluorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Difluorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2-chloro-3-fluorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-ethyl-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-cyclopropyl-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2(2,3-Dichlorophenoxymethyl)-8-methyl-isopropyl-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S-2-(1-Naphthyloxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Chlorophenylthiomethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2S,3R)-2-(2,3-Dichloro-phenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2S,3R)-2-(1-Naphthyloxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane-   (2S,3R)-2-(2,3-Chlorophenylthiomethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(n-butyl)8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dichlorophenylthiomethyl)-8-H-3-n-butyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dimethoxyphenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-fluorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Difluorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2-Chloro-3-fluorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-ethyl-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-cyclopropyl-8-aza-bicyclo[3.2.1]octane;-   (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-isopropyl-8-aza-bicyclo[3.2.1]octane;    or any of its isomers or any mixture of its isomers, or a    pharmaceutically acceptable salt thereof.

Any combination of two or more of the embodiments as described above isconsidered within the scope of the present invention.

Definition of Substituents

In the context of this invention halo represents fluoro, chloro, bromoor iodo.

In the context of this invention an alkyl group designates a univalentsaturated, straight or branched hydrocarbon chain. The hydrocarbon chainpreferably contain of from one to six carbon atoms (C₁₋₆-alkyl),including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl andisohexyl. In a preferred embodiment alkyl represents a C₁₋₄-alkyl group,including butyl, isobutyl, secondary butyl, and tertiary butyl. Inanother preferred embodiment of this invention alkyl represents aC₁₋₃-alkyl group, which may in particular be methyl, ethyl, propyl orisopropyl.

In the context of this invention an alkenyl group designates a carbonchain containing one or more double bonds, including di-nes, tri-enesand poly-enes. In a preferred embodiment the alkenyl group of theinvention comprises of from two to six carbon atoms (C₂₋₆-alkenyl),including at least one double bond. In a most preferred embodiment thealkenyl group of the invention is ethenyl; 1- or 2-propenyl; 1-, 2- or3-butenyl, or 1,3-butdiynyl; 1-, 2-, 3-, 4- or 5-hexenyl, or1,3-hexdienyl, or 1,3,5-hextrienyl.

In the context of this invention an alkynyl group designates a carbonchain containing one or more triple bonds, including di-ynes, tri-ynesand poly-ynes. In a preferred embodiment the alkynyl group of theinvention comprises of from two to six carbon atoms (C₂₋₆-alkynyl),including at least one triple bond. In its most preferred embodiment thealkynyl group of the invention is ethynyl; 1-, or 2-propynyl; 1-, 2-, or3-butynyl, or 1,3-butdiynyl; 1-, 2-, 3-, 4-pentynyl, or 1,3-pentdiynyl;1-, 2-, 3-, 4-, or 5-henynyl, or 1,3-hexdiynyl or 1,3,5-hextriynyl.

In the context of this invention a cycloalkyl group designates a cyclicalkyl group, preferably containing of from three to seven carbon atoms(C₃₋₇-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

Alkoxy is O-alkyl, wherein alkyl is as defined above.

Cycloalkoxy means O-cycloalkyl, wherein cycloalkyl is as defined above.

Cycloalkylalkyl means cycloalkyl as above and alkyl as above, meaningfor example, cyclopropylmethyl.

Amino is NH₂ or NH-alkyl or N-(alkyl)₂, wherein alkyl is as definedabove.

Pharmaceutically Acceptable Salts

The chemical compound of the invention may be provided in any formsuitable for the intended administration. Suitable forms includepharmaceutically (i.e. physiologically) acceptable salts, and pre- orprodrug forms of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic Inorganic and organic add addition salts suchas the hydrochloride derived from hydrochloric acid, the hydrobromidederived from hydrobromic add, the nitrate derived from nitric acid, theperchlorate derived from perchloric add, the phosphate derived fromphosphoric acid, the sulphate derived from sulphuric add, the formatederived from formic add, the acetate derived from acetic acid, theaconate derived from aconitic acid, the ascorbate derived from ascorbicadd, the benzenesulphonate derived from benzensulphonic add, thebenzoate derived from benzoic add, the cinnamate derived from cinnamicadd, the citrate derived from citric acid, the embonate derived fromembonic add, the enantate derived from enanthic acid, the fumaratederived from fumaric add, the glutamate derived from glutamic add, theglycolate derived from glycolic add, the lactate derived from lacticadd, the maleate derived from maleic add, the malonate derived frommalonic add, the mandelate derived from mandelic add, themethanesulphonate derived from methane sulphonic add, thenaphthalene-2-sulphonate derived from naphtalene-2-sulphonic add, thephthalate derived from phthalic add, the salicylate derived fromsalicylic add, the sorbate derived from sorbic acid, the stearatederived from stearic add, the succinate derived from succinic acid, thetartrate derived from tartaric acid, the toluene-p-sulphonate derivedfrom p-toluene sulphonic add, and the like. Such salts may be formed byprocedures well known and described in the art. Other adds such asoxalic acid, which may not be considered pharmaceutically acceptable,may be useful in the preparation of salts useful as intermediates inobtaining a chemical compound of the invention and its pharmaceuticallyacceptable add addition salt

Metal salts of a chemical compound of the invention include alkali metalsalts such as the sodium salt of a chemical compound of the inventioncontaining a carboxy group.

In the context of this invention the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts.Preferred “onium salts” include the alkyl-onium salts, thecycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

Examples of pre- or prodrug forms of the chemical compound of theinvention include examples of suitable prodrugs of the substancesaccording to the invention include compounds modified at one or morereactive or derivatizable groups of the parent compound. Of particularinterest are compounds modified at a carboxyl group, a hydroxyl group,or an amino group. Examples of suitable derivatives are esters oramides.

The chemical compound of the invention may be provided in dissoluble orindissoluble forms together with a pharmaceutically acceptable solventsuch as water, ethanol, and the like. Dissoluble forms may also includehydrated forms such as the monohydrate, the dihydrate, the hemihydrate,the trihydrate, the tetrahydrate, and the like. In general, thedissoluble forms are considered equivalent to indissoluble forms for thepurposes of this invention.

Steric Isomers

It will be appreciated by those skilled in the art that the compounds ofthe present invention may contain one or more chiral centers, and thatsuch compounds exist in the form of isomers, i.e. 1R/S, 2R/S, 3R/S and5R/S.

Moreover, the substituent —CH₂—X—R^(a) on position 2 and the substituentR³ on position 3 of the 8-aza-bicyclo[3.2.1]octane skeleton of formula Imay in particular be in cis or trans configuration relative to eachanother. In a preferred embodiment of the invention the substituents atpositions 2 and 3 are in trans configuration. In another preferredembodiment of the invention the substituents at positions 2 and 3 are incis configuration.

The invention includes all such isomers and any mixtures thereofincluding racemic mixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the isomeric salts is byuse of an optically active acid, and liberating the optically activeamine compound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptical active matrix. Racemic compounds of the present invention canthus be resolved into their optical antipodes, e.g., by fractionalcrystallisation of d- or l-(tartrates, mandelates, or camphorsulphonate)salts for example.

The chemical compounds of the present invention may also be resolved bythe formation of diastereomeric amides by reaction of the chemicalcompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe art Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

Labelled Compounds

The compounds of the invention may be used in their labelled orunlabelled form. In the context of this invention “label” stands for thebinding of a marker to the compound of interest that will allow easyquantitative detection of said compound.

The labelled compounds of the invention may be useful as diagnostictools, radio tracers, or monitoring agents in various diagnosticmethods, and for in vivo receptor imaging.

The labelled isomer of the invention preferably contains at least oneradionuclide as a label. Positron emitting radionuclides are allcandidates for usage. In the context of this invention the radionuclideis preferably selected from ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C,¹³¹I, ¹²⁵I, ¹²³I, and ¹⁸F.

The physical method for detecting the labelled isomer of the presentinvention may be selected from Position Emission Tomography (PET),Single Photon Imaging Computed Tomography (SPECT), Magnetic ResonanceSpectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed AxialX-ray Tomography (CAT), or combinations thereof.

Methods of Preparation

The chemical compounds of the invention may be prepared by conventionalmethods for chemical synthesis, e.g. those described In the workingexamples. The starting materials for the processes described in thepresent application are known or may readily be prepared by conventionalmethods from commercially available chemicals.

Also one compound of the invention can be converted to another compoundof the invention using conventional methods.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Biological Activity

Compounds of the invention may be tested for their ability to inhibitreuptake of the monoamines dopamine, noradrenaline and serotonin insynaptosomes eg such as described in WO 97/30997. Based on the balancedactivity observed in these tests the compound of the invention isconsidered useful for the treatment the treatment, prevention oralleviation of a disease or a disorder or a condition of a mammal,including a human, which disease, disorder or condition is responsive toinhibition of monoamine neurotransmitter re-uptake in the centralnervous system.

In a special embodiment, the compounds of the invention are considereduseful for the treatment, prevention or alleviation of: mood disorder,depression, atypical depression, major depressive disorder, dysthymicdisorder, bipolar disorder, bipolar I disorder, bipolar II disorder,cyclothymic disorder, mood disorder due to a general medical condition,substance-induced mood disorder, pseudodementia, Ganser's syndrome,obsessive compulsive disorder, panic disorder, panic disorder withoutagoraphobia, panic disorder with agoraphobia, agoraphobia withouthistory of panic disorder, panic attack, memory deficits, memory loss,attention deficit hyperactivity disorder, obesity, anxiety, generalizedanxiety disorder, eating disorder, Parkinson's disease, parkinsonism,dementia, dementia of ageing, senile dementia, Alzheimer's disease,acquired immunodeficiency syndrome dementia complex, memory dysfunctionin ageing, specific phobia, social phobia, post-traumatic stressdisorder, acute stress disorder, drug addiction, drug misuse, cocaineabuse, nicotine abuse, tobacco abuse, alcohol addiction, alcoholism,pain, inflammatory pain, neuropathic pan, migraine pain, tension-typeheadache, chronic tension-type headache, pain associated withdepression, fibromyalgia, arthritis, osteoarthritis, rheumatoidarthritis, back pain, cancer pain, irritable bowel pain, irritable bowelsyndrome, post-operative pain, post-stroke pain, drug-inducedneuropathy, diabetic neuropathy, sympathetically-maintained pain,trigeminal neuralgia, dental pain, myofacial pain, phantom-limb pain,bulimia, premenstrual syndrome, late luteal phase syndrome,post-traumatic syndrome, chronic fatigue syndrome, urinary incontinence,stress incontinence, urge incontinence, nocturnal incontinence,premature ejaculation, erectile difficulty, anorexia nervosa, sleepdisorders, autism, mutism, trichotillomania, narcolepsy, post-strokedepression, stroke-induced brain damage, stroke-induced neuronal damageor Gilles de la Tourettes disease. In a preferred embodiment, thecompounds are considered useful for the treatment, prevention oralleviation of depression.

It is at present contemplated that a suitable dosage of the activepharmaceutical ingredient (API) is within the range of from about 0.1 toabout 1000 mg API per day, more preferred of from about 10 to about 500mg API per day, most preferred of from about 30 to about 100 mg API perday, dependent, however, upon the exact mode of administration, the formin which it is administered, the indication considered, the subject andin particular the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

Preferred compounds of the invention show a biological activity in thesub-micromolar and micromolar range, i.e. of from below 1 to about 100μM.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of thechemical compound of the invention.

While a chemical compound of the invention for use in therapy may beadministered in the form of the raw chemical compound, it is preferredto introduce the active ingredient, optionally in the form of aphysiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers, buffers,diluents, and/or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the chemical compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers therefore, and,optionally, other therapeutic and/or prophylactic ingredients, know andused in the art. The carrier(s) must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and notharmful to the recipient thereof.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, bronchial, nasal, pulmonal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (including cutaneous,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection or infusion)administration, or those in a form suitable for administration byinhalation or insufflation, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsules.

The chemical compound of the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof. Such forms includesolids, and in particular tablets, filled capsules, powder and pelletforms, and liquids, in particular aqueous or non-aqueous solutions,suspensions, emulsions, elixirs, and capsules filled with the same, allfor oral use, suppositories for rectal administration, and sterileinjectable solutions for parenteral use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The chemical compound of the present invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a chemical compound of the invention ora pharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations, intended for conversionshortly before use to liquid form preparations for oral administration.Such liquid forms include solutions, suspensions, and emulsions. Inaddition to the active component such preparations may is comprisecolorants, flavours, stabilisers, buffers, artificial and naturalsweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the chemical compound of theinvention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the aboveingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient In a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented In unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

A therapeutically effective dose refers to that amount of activeingredient, which ameliorates the symptoms or condition. Therapeuticefficacy and toxicity, e.g. ED₅₀ and LD₅₀, may be determined by standardpharmacological procedures in cell cultures or experimental animals. Thedose ratio between therapeutic and toxic effects is the therapeuticindex and may be expressed by the ratio LD₆₀/ED₅₀. Pharmaceuticalcompositions exhibiting large therapeutic indexes are preferred.

The dose administered must of course be carefully adjusted to the age,weight and condition of the Individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired, and the exact dosage should of course be determined by thepractitioner.

The actual dosage depend on the nature and severity of the disease beingtreated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

In another aspect the invention provides a method for the treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disease, disorder orcondition is responsive to inhibition of monoamine neurotransmitterre-uptake in the central nervous system, and which method comprisesadministering to such a living animal body, including a human, in needthereof an effective amount of a chemical compound of the invention.

It is at present contemplated that suitable dosage ranges are 0.1 to1000 milligrams daily, 10-500 milligrams daily, and especially 30-100milligrams daily, dependent as usual upon the exact mode ofadministration, form in which administered, the indication toward whichthe administration is directed, the subject involved and the body weightof the subject involved, and further the preference and experience ofthe physician or veterinarian in charge.

EXAMPLES

The invention is further illustrated with reference to the followingexamples, which are not intended to be in any way limiting to the scopeof the invention as claimed.

Starting Materials

(+)-2-Carbomethoxytropinone

Was prepared by a known procedure (J. F. Casale, Forensic ScienceInternational, 33 (1987) 275-298).

(−)-2-Carbomethoxytropinone

Was synthesized similarly.

Method A

(−)-Ecgonine ethylester

To a stirred solution of (+)-2-carbomethoxytropinone (37.4 g) in methylalcohol (1.5 L) at −45° C., was added sodium borohydride (37 g) in smallportions, such that the internal temperature was kept between −45° C.and −35° C. The reaction mixture was stirred at −45° C. for 2 hours, andquenched by drop wise addition of hydrochloric acid (120 mL), whilekeeping the temperature at −45° C. The reaction mixture was allowed towarm to room temperature and stirred overnight. The reaction mixture wasconcentrated to a volume of approximately 120 mL, added water (500 mL)and washed with diethyl ether (3×100 mL). The aqueous phase was added25% ammonia (aq.) until pH 10-11, and extracted with dichloromethane(4×200 mL). The combined organic phases were dried (sodium sulfate) andevaporated to an oil. The oil was dissolved in ethyl acetate (370 mL)and a solution of sodium ethoxide (from 7 g of sodium) was added. Theresulting solution was heated at reflux for 3 hours, cooled to r.t. andevaporated to an oil. The residue was added toluene (0.5 L) andevaporated to an oil, this was repeated. The product 30 g (79%) is anoil.

(+)-Ecgonine ethylester

Was synthesised similarly (−)-2-carbomethoxytropinone.

Method B

(2R,3S)-8-Methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylicacid ethyl ester

A solution of (−)ecgonine ethylester (26 g; 130 mmol) in anhydroustoluene (150 mL) was added to a stirred solution of3-chlorophenylmagnesium bromide (48 mmol) in anhydrous Et₂O (200 mL) at−20° C., such that the internal temperature was kept between −15° C. and−25° C. The reaction mixture was stirred at −15° C. to −25° C. for 60min, or until TLC indicated complete transformation of startingmaterial. The reaction mixture was poured onto a mixture of conc. HCl(40 mL) and ice (250 mL) and stirred for 20 min. The aqueous phase waswashed with Et₂O (50 mL), and made alkaline to pH 10-11 using 4 M NaOH,below 20° C. The aqueous phase was extracted using CH₂Cl₂ (3×100 mL) andthe combined organic fractions dried (MgSO₄), filtered and evaporated todryness to yield 39.9 g (99%) of an oil. A mixture of the crude oil,NaOMe (10 ml, 2 M) and anhydrous MeOH (250 mL) was refluxed for 70 h andthen evaporated to dryness. Water (100 mL) was added, and extractedusing diethyl ether (3×100 mL). The combined organic fractions weredried (MgSO₄), filtered and evaporated to dryness to yield 32.7 g (85%)as an oil.

(2S,3R)-8-Methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylicacid ethyl ester

Was synthesised similarly from (+)-ecgonine ethylester.

Method C

(2R,3S)-(8-Methyl-3-(3-chlorophenyl-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol

To a mixture of(2R,3S)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylicacid ethyl ester (32.7 g, 110 mmol) and toluene (200 ml), Red-Al (40 g,65%, 128 mmol) was added at 0° C. The mixture was stirred at roomtemperature for 1 h. A solution of aqueous sodium hydroxide (80 ml, 4 M)was added dropwise to the cooled mixture, followed by warm water (50°C., 150 ml). The mixture was extracted with toluene (2×100 ml). Themixture was dried (MgSO₄) and evaporated. The product was isolated ascrystals. Mp 180.4° C. Yield 17.1 g (59%).

(2S,3R)-(8-Methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol

Was synthesised similarly from(2S,3R)8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylicacid ethyl ester.

The following compounds were prepared analogously using theabove-described methods:

-   (2R,3S)-(8-methyl-3-(3-n-butyl)-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.    Mp 94.5-96.5° C.-   (2R)-(8-methyl-aza-bicyclo[3.2.1]oct-2-yl)-methanol. Mp 78.5-80.0°    C.-   (2R,3S)-(8-methyl-3-(3-fluorophenyl)-aza-bicyclo[3.2.1]oct-2-yl)-methanol.    Mp 196° C.-   (2R,3S)-(8-methyl-3-methyl-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.    Mp 50–55° C.-   (2R,3S)-(8-methyl-3-cyclopropyl-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.    Mp 106–141° C.-   (2R,3S)-(8-methyl-3-isopropyl-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.    Mp 130.6–135.9° C.    Method D

(2R,3S)-2-(2,3-Dichlorophonoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

A mixture of(2R,3S)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol(15.1 g; 57 mmol), p-toluenesulfonylchloride (13.0 g; 68 mmol), pyridine(50 ml) was stirred for 10 minutes at 0° C., followed by stirring 5 h atroom-temperature. The reaction mixture was added H₂O (250 mL), aqueoussodium hydroxide (25 ml, 4 M) and the crystalline O-tosylatedintermediate was isolated by filtration and triturated with water. Yield22.76 g (95%) of the O-tosylated intermediate. To a stirred mixture of2,3-dichlorophenol (1.63 g; 10 mmol) and O-tosylated intermediate (3.0g, 7.0 mmol) in DMF (20 mL) was added NaH (0.4 g, 60%, 10 mmol). Thereaction mixture was heated to 100° C. for 3 h. The reaction mixture wascooled to rt, and water (50 ml) was added. The mixture was extractedwith Et₂O (2×50 mL). The combined organic fractions were dried (MgSO₄),filtered and evaporated to dryness. Column chromatography(acetone:MeOH:NH₃ (1% aq.)=9:1:1) yielded 1.51 mg (52%) product. Thefree base was converted to the fumaric acid salt Mp: 133.6° C.

(2R,3S)-2-(1-Naphthaleneoxymethyl)-8-methyl-3-(3-chlorophonyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method D from(2S,3R)-(8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]oct-2-yl)methanol.Mp 203.1° C.

(2R,3S)-2-(2,3-Chlorophenylthiomethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method D from(2R,3S)-8-methyl-3-(3-chlorophenyl)-(8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.Mp 131.7-150.1° C.

(2S,3R)-2-(2,3-Dichloro-phenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane

Is synthesised similarly from(2S,3R)-(8-(methyl-3-(-3-chlorophenyl)-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.

(2S,3R)-2-(1-Naphthaleneoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane

Is synthesised similarly from(2S,3R)-(8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.

(2S,3R)-2-(2,3-Chlorophenylthiomethy)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane

Is synthesised similarly from(2S,3R)-(8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.

(2R,3S)-2(2,3-Dichlorophenoxymethyl)8-methyl-3-(n-butyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method D from(2R,3S)-(8-methyl-3-(3-n-butyl)-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.Mp 60-70° C.

(2R,3S)-2-(1-Napthyloxymethyl)-8-methyl-3-(n-butyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method D from(2R,3S)-(8-methyl-3-(3-n-butyl)-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.Mp 60-70° C.

(2R,3S)-2-(2,3-Dichlorophenylthiomethyl)-8-methyl-3-(n-butyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method D from(2R,3S)-(8-methyl-3-(3-n-butyl)-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.Mp 40-50° C.

(2R,3S)-2-(2,3-Dimethoxyphenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method D from(2R,3S)-(8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.Mp 70.7° C.

(2R)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method D from(2R)-(8-methyl-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol. Mp 135-137° C.

(2R)-2-(1-Naphthyloxymethyl)-8-methyl-8-aza-bicyclo[3.2.1]octane fumaricacid salt

Was prepared according to method D from(2R)-(8-methyl-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol. Mp 147-149° C.

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-fluorophenyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method D from(2R,3S)-(8-methyl-3-(3-fluorophenyl)-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.Mp 196.3° C.

(2R,3S)-2-(2,3-Difluorophanoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method D from(2R,3S)-(8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.Mp 62.5-73.9° C.

(2R,3S)-2-(2-chloro-3-fluorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method D from(2R,3S)-(8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.Mp 123° C.

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-ethyl-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method D from(2R,3S)-(8-methyl-3-ethyl-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol. Oil.

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-cyclopropyl-8-aza-bicyclo[3.2.1]octanecitric acid salt

Was prepared according to method D from(2R,3S)-(8-methyl-3-cyclopropyl-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol.Mp 106-141° C.

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-isopropyl-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method D from(2R,3S)-(8-methyl-3-isopropyl-8-aza-bicyclo[3.2.1]oct-2-yl)-methanol. Mp74.4-75.0° C.

Method E

(2R,3S)2-(2,3-Dichlorophenoxymethyl)-8-H-3-(chlorophenyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

A mixture of(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane(1.27 g, 3.09 mmol), 1-chloroethylchloro-formate (1.66 ml, 15.4 mmol)and toluene (30 ml) was stirred for 0.5 h at room temperature. Themixture was stirred at 100° C. for 20 h. Water (25 ml) was added and themixture was stirred at reflux for 4 h. The mixture was allowed to reachroom temperature and ammonia (50 ml, 1 M) was added followed byextraction with diethylether (3×50 ml). The crude product was purifiedby column chromatography using silica gel and a mixture ofdichloromethane:methanol:aqueous ammonia (90:9:1) as liquid phase. Theresulting oil (0.79 g, 2.0 mmol) was converted to the fumaric acid saltby stirring in ethanol (025 ml) and fumaric acid (025 g, 1.5 mmol),followed cooling and filtration. Yield 0.79 (77%). Mp: 204.6° C.

(2R,3S)-2-(1-naphthyloxymethyl)-8-H-3-(3-chlorophonyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method E from(2R3S)-2-(1-naphthyloxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane.Mp: 199.1° C.

(2R,3S)-2-(2,3-Chlorophenylthiomethyl)-8-H-3-(3-chlorophonyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method E from(2R,3S)-2-(2,3-dichlorophenylthiomethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane.Mp: 175° C.

(2S,3R)-2-(2,3-Dichloro-phenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane

Is synthesised similarly from(2S,3R)-2-(2,3Dichloro-phenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane.

(2S,3R)-2-(1-naphthyloxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane

Is synthesised similarly from(2S,3R)-2-(1-naphthyloxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane.

(2S,3R)-2-(2,3-Chlorophenylthiomethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane

Is synthesised similarly from(2S,3R)-2-(2,3-dichlorophenylthiomethyl)-8-methyl-3(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane.

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(n-butyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method E from(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-(3-n-butyl)-8-aza-bicyclo[3.2.1]octaneMp 160-163° C.

(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(n-butyl)-8a-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method E from(2R,3S)-2-(1-naphthyloxymethyl)-8-methyl-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane.Mp 108-110° C.

(2R,3S)-2-(2,3-Dichlorophenylthiomethyl)-8-H-3(n-butyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method E from(2R,3S)-2-(2,3-dichlorophenylthiomethyl)-8-methyl-3-(n-butyl-8-aza-bicyclo[3.2.1]octane.Mp 108-110° C.

(2R,3S)-2-(2,3-Dimethoxyphenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method E from(2R3S)-2-(2,3-dimethoxyphenoxy-methyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octaneMp 173.6-191.6° C.

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-fluorophenyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method E from(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-fluorophenyl)-8-aza-bicyclo[3.2.1]octaneMp 183.4-186.5° C.

(2R,3S)-2-(2,3-Difluorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method E from(2R,3S)-2-(2,3-difluorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octaneMp 200.7-204.5° C.

(2R,3S)-2-(2-Chloro-3-fluorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method E from(2R,3S)-2-(2-chloro-3-fluorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octaneMp 183.5-185.5° C.

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-ethyl-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method E from(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-ethyl-8-aza-bicyclo[3.2.1]octaneMp 143-145° C.

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-cyclopropyl-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method E from(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-cyclopropyl-8-aza-bicyclo[3.2.1]octaneMp 178.1-185.7° C.

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-isopropyl-8-aza-bicyclo[3.2.1]octanefumaric acid salt

Was prepared according to method E from(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-isopropyl-8-aza-bicyclo[3.2.1]octaneMp 200-203° C.

TEST EXAMPLES

In Vitro Inhibition Activity

A number of compounds were tested for their ability to Inhibit thereuptake of the monoamine neurotransmitters dopamine (DA)noradrenaline(NA) and serotonin (5-HT) in synaptosomes as described inWO 97/16451.

The test values are given as IC₅₀ (the concentration (μM) of the testsubstance which inhibits the specific binding of ³H-DA, ³H-NA, or3H-5-HT by 50%).

Test results obtained by testing selected compounds of the presentinvention appear from the below table:

TABLE 1 DA- NA- 5-HT- uptake uptake uptake Test compound IC₅₀(μM)IC₅₀(μM) IC₅₀(μM) 1st compound of method D; 0.062 0.035 0.00072(2R,3S)-2-(2,3- Dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza- bicyclo[3.2.1]octane fumaric acidsalt 2nd compound of method D; 0.065 0.15 0.0063 (2R,3S)-2-(1-Naphthaleneoxymethyl)-8-methyl-3- (3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt 1st compound of method E; 0.100.048 0.0062 (2R,3S)-2-(2,3- Dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza- bicyclo[3.2.1]octane fumaric acid salt 2ndcompound of method E; 0.088 0.051 0.013 (2R,3S)-2-(1-naphthyloxymethyl)-8-H-3-(3-chlorophenyl)-8-aza- bicyclo[3.2.1]octane fumaric acid salt

1. A chemical compound which is an 8-aza-bicyclo[3.2.1]octane derivativeof the Formula I:

or any of its stereoisomers or any mixture of its stereoisomers, or apharmaceutically acceptable salt thereof, wherein R represents hydrogenor alkyl; R² represents —CH₂—X—R^(a); wherein X represents —O— or —S—;R^(a) represents

wherein R^(b) and R^(c) are independently selected from the groupconsisting of: halo, hydroxy, amino, cyano, nitro, trifluoromethyl,trifluoromethoxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, and alkynyl; or R^(a) represents naphthyl;which naphthyl is optionally with substituted with one or moresubstituents selected from the group consisting of: halo, hydroxy,amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkoxy,cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, and alkynyl;and R³ represents phenyl or naphthyl; which phenyl or naphthyl isoptionally substituted with one or more substituents selected from thegroup consisting of: halo, hydroxy, amino, cyano, nitro,trifluoromethyl, trifluoromethoxy, alkoxy, cycloalkoxy, alkyl,cycloalkyl, cycloalkylalkyl, alkenyl, and alkynyl; or R³ representshydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, or alkynyl; whichalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, or alkynyl is optionallysubstituted with one or more substituents from the group consisting of:halo, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy,alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, andalkynyl.
 2. The chemical compound of claim 1, wherein R representshydrogen or methyl.
 3. The chemical compound of claim 1, wherein R^(a)represents

wherein R^(b) is halo and R^(c) is halo.
 4. The chemical compound ofclaim 1, wherein R^(a) represents

wherein R^(b) is alkoxy and R^(c) alkoxy.
 5. The chemical compound ofclaim 1, wherein R^(a) represents naphthyl.
 6. The chemical compound ofclaim 1, wherein R³ represents phenyl optionally substituted with one ormore halo.
 7. The chemical compound of claim 1, wherein R³ representshydrogen, alkyl or cycloalkyl.
 8. The chemical compound of claim 1,wherein R represents hydrogen or methyl; R^(a) represents2,3-dihalophenyl, 2,3-dimethoxyphenyl or naphthyl; and R³ representshydrogen, alkyl, cycloalkyl or phenyl optionally substituted with one ormore halo.
 9. The chemical compound of claim 1, which is(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(1-Naphthaleneoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Chlorophenylthiomethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2S,3R)-2-(2,3-Dichloro-phenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2S,3R)-2-(1-Naphthaleneoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2S,3R)-2-(2,3-Chlorophenylthiomethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dichlorophenylthiomethyl)-8-methyl-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dimethoxyphenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-8-aza-bicyclo[3.2.1]octane;(2R)-2-(1-Naphthyloxymethyl)-8-methyl-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-fluorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Difluorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2-chloro-3-fluorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-ethyl-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-cyclopropyl-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-isopropyl-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Chlorophenylthiomethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]-octane;(2S,3R)-2-(2,3-Dichloro-phenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2S,3R)-2-(1-Naphthyloxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2S,3R)-2-(2,3-Chlorophenylthiomethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dichlorophenylthiomethyl)-8-H-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dimethoxyphenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-fluorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Difluorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2-Chloro-3-fluorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-ethyl-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-cyclopropyl-8-aza-bicyclo[3.2.1]octane;(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-isopropyl-8-aza-bicyclo[3.2.1]octane;or any of its stereoisomers or any mixture of its stereoisomers, or apharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundof claim 1, or any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, excipient or diluent.